1. Field of the Invention
Generally, the present invention relates to the field of therapeutic agents. More specifically, the present invention relates to a hydrogels containing therapeutic agents.
2. Description of the Related Art
Dendrimers are a class of well-defined nanostructured macromolecules with narrow polydispersity, and a multivalent surface amenable for further modifications. Dendrimers are extensively and continually investigated for biomedical applications such as gene therapy, drug delivery and bioimaging purposes. As nanocarriers, dendrimers have the versatility to allow conjugation, complexation, and/or encapsulation of multifunctional moieties. The functional groups on the periphery of dendrimer act as highly accessible handles for drug or other functional group attachments. Since the functionalities of the drugs and ligands are diverse, there is a need to explore multiple functional group presentations at the dendrimer surface. Adding diverse functional moieties (drugs or imaging agents) onto a single dendrimer is difficult because all the peripheral groups of the symmetric dendrimer have the same reactivity. A suitable linker or spacer is required to react with the surface functionality of dendrimer, which offers the flexibility to link multiple moieties-such as drugs, imaging or targeting agents.
Functionalization of dendrimers has enabled several end objectives like reduction in cytotoxicity, targeted drug delivery, formation of hydrogels, increase plasma residence time, imaging, in-vivo biodegradation, or potentially any combination of these. For example, modification of G4 dendrimers with 19, 29, 46 molecules of phenylalanine resulted in improved gene transfection ability, while modification with 64 molecules of phenylalanine resulted in poorly soluble compounds with loss in DNA complexing ability. Widespread use of cationic dendrimers in drug and gene delivery is hindered by their cytotoxicity. PEGylation and acetylation are highly successful approaches in overcoming the cytotoxicity of amine terminated dendrimers but the higher degree of amine neutralization compromises its gene slicing efficiency. The dendrimer surface modification should therefore be such that several end objectives are met without compromising on any attributes and yet having chemically reactive groups suitable for modifications to attach drug or targeting moieties. There is a need to develop new methodologies for synthesis of functionalized dendrimers that involve fewer reaction steps, achieve high yields, are compatible with a variety of functional groups, and occur under mild reaction conditions offering clean and efficient synthesis.
To make dendrimers as efficient delivery vectors, apart from multivalency there is a need to have unique orthogonal end groups for chemoselective surface modifications and multi-functionalization. There are studies described in the literature for development of hetero-bifunctional dendrimers. However, the research into development of such dendrimers for biomedical applications is not extensive. The dendrimer synthesis requires elaborate steps, and is expensive, thereby limiting the commercial availability to PAMAM, DAB, Phosphorous PMMH and 2,2-bis(methylol)propionic acid (bis-MPA) dendrimers. There have been few reports on the synthesis of dendrimers bearing different asymmetric groups at the periphery. It is reported that to obtain a total of 32 (16+16) and 48 (24+24) reactive groups on the generation 4 dendrimer several sequential steps were required. Previously, melamine dendrimers with orthogonal reactive groups on surface comprising 4 hydroxyl groups, 4 hydroxyl groups masked as tert-butyldiphenylsilyl ether and 16 tert-Butoxycarbonyl protected amines was synthesized in eight total steps with a 55% overall yield. An efficient method to synthesize dendrimers with orthogonal peripheral groups is to grow a symmetric dendrimer in bulk and then tune its periphery for the desired application. However, this process requires that the subsequent differentiation and coupling steps be minimal in number and efficient in reactivity.
Functionalization of the peripheral groups of dendrimers is an extremely fruitful and convenient strategy for developing novel functional materials for biomedical applications and ways to simplify the synthesis towards achieving would be beneficial. For the application of dendrimers in drug delivery and biomedical area there is a need to develop these scaffolds with biocompatible (or generally recognized as safe materials by US FDA) materials such that their metabolites are non-toxic. Since dendrimers offer multivalency, one of the advantages is to use the functional handles to append diverse functional groups such as different drug molecules and imaging agents. However, these functional groups bear different reactive groups and to append these on dendrimers there is a need to undergo several synthetic steps for attachment of specific linkers or spacer molecule. Hence there is a need to have a dendrimer with biocompatible orthogonal groups that facilitate chemoselective attachment of these functional groups in minimal synthetic steps.